Acetone-1,3-dicarboxylic acid

The reaction must be carried out in a good hood, since a large amount of carbon monoxide is liberated. 

The use of a very efficient ice and salt mixture around the reaction flask is necessary if the reaction is to be carried out within the time indicated. It is very necessary to regulate the temperature as directed, since a considerably lower yield is obtained if the temperature rises. 

Some cooling is necessary, or the rapid evolution of gas will cause the reaction mixture to foam over with consequent loss of material. 

Vigorous cooling before final filtration of the acetone 

The filtros plate for filtration can be very conveniently sealed into the Buchner funnel with a paste of water-glass and amorphous silica which is then hardened with concentrated sulfuric acid. 

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Sulphuric add test. Heat 0 5 g. of citric acid or a citrate with 1 ml. of H2SO4 CO and COg are evolved and the mixture turns yellow, but does not char. Acetone dicarboxylic acid, OC(CH2COOH)g, is also formed, and is tested for after heating the mixture for 1 minute cool, add a few ml. of water and make alkaline with NaOH solution. Add a few ml. of a freshly prepared solution of sodium nitroprusside and note the intense red coloration (see Test 4 a) for ketones, p. 346). 

Further studies by Spenser demonstrated that l,2-13C-labeled acetate (13) was incorporated into lycopodine but gave a distribution of the labels that did not account for the pelletierine-route that was hypothesized (Scheme 6.2) [11]. An intact 3-carbon unit was desired for testing, but labeled acetoacetate (l,2,3,4-13C-acetoacetate (14), which could undergo decarboxylation to provide an intact 3-carbon unit) was found to give the same incorporation pattern as acetate (and therefore must have been cleaved to acetate prior to uptake). In addition, feeding studies using deuterated, 13C-labeled acetate provided a loss or washout of deuterium at the C16 methyl group. This could only occur if an intermediate had formed that would provide for facile enolization. Both the equal distribution of the 13C labels and loss of the deuteriums led the researchers to propose that the intermediate was symmetric, such as acetone dicarboxylic acid (15). 

To a mixture of 360 g 50% KOH and 138 ml methanol, add with stirring at -5° 70.5 g dimethyl ester of acetone dicarboxylic acid (dimethyl-beta-ketoglutarate — see method 3 for preparation) and let temperature rise to about 25° over V2 hour. Let stand ten minutes, cool to 0° and add 65 ml ether. Filter, wash precipitate with 65 ml ethanol and 150 ml ether at 0C to get 75 g (III). To 322 ml 1N HCI at 80c, add 41.1 g (I I) and stir twenty minutes cool to 10°, add 211 ml IN HCI, 98.2 g (Ml). 26.4 g Na acetate and 28.2 g methylamine HCI. Stir four hours at room temperature, cool to 10°, and saturate with 410 g KOH. Extract four times with methyl-Cl or benzene (75 ml each, fifteen minutes stirring) and evaporate in vacuum to get the methyl ester of tropan-3-one-2-COOH (IV), which precipitates from the oil (can distill 85/0,2). Test for activity. Dissolve 28.3 g (IV) in 170 ml 10% sulfuric acid cool to -5° and treat with 3.63 kg 1.5% Na-Hg amalgam with vigorous stirring at 0°. See below for easier methods of reducing (IV),... 

Acetic Anhydride Acetone Dicarboxylic Acid N-Acetylanthranilic Acid N-Acetylmescaline Aluminum Foil ( ) Ammonium Acetate Anthranilic Acid Barbituric Acid Benzaldehyde Benzocaine... 

Acetone dicarboxylic acid was first obtained by the action of concentrated sulfuric acid upon citric acid.1 It has been made also by the gradual decomposition of a mixture of lime and sucrose.2 The most satisfactory method, however, for producing this substance, is by the action of fuming sulfuric acid upon citric acid. Details of this preparation have been modified a number of times with the intention of improving the yield.3... 

The crude acetone dicarboxylic acid ontained from 700 g. of citric acid, as described on page 5, is treated with 700 g. of absolute ethyl alcohol (Note 1) to which has been added at least 130-150 g. of dry hydrogen chloride. The mixture is placed in a flask fitted with a stopper holding a calcium chloride tube and then is heated to 450. It is kept in a water bath at 450 (bath temperature) with frequent shaking until all of the acid is dissolved (fifteen to twenty minutes). The solution is allowed to cool down to room temperature in the bath and finally to stand about twelve hours (Note 2). 

This was a famous synthesis because it is so short and simple and also because it makes a natural product in a way that imitates nature. The reaction is carried out at pH 7 in water. In fact Robinson didn t use acetone, as suggested by his imaginary hydrolysis , but acetone dicarboxylic acid. This procedure is an improved one invented by Schopf2 in 1935. 

Acetylmalonic Acid, CH3 CO CH (COOH) 2, and Acetone-dicarboxylic Acid, CO (CH2COOH) 2, do not permit their anions to unite (Weems2). 

This complex route to tropinone was imitated as long ago as 1917 in one of the most celebrated reactions of all time, Robinson s tropinone synthesis. Robinson argued on purely chemical grounds that the sequence of imine salts and enols, which later (1970) turned out to be Nature s route, could be produced under natural conditions (aqueous solution at pH 7) from a C4 dialdehyde, MeNH2 and acetone dicarboxylic acid. It worked and the intermediates must be very similar to those in the biosynthesis. 

Pyrrolidines can also be prepared by Mannich reactions a classical example is the synthesis of tropinone 43 from succindialdehyde, methylamine, and acetone dicarboxylic acid (Scheme 32) <1917JCS762> reactions of this type are involved in alkaloid biogenesis. 

This ester has been prepared by the esterification of acetone dicarboxylic acid 1 and of ethyl 7-cyanoacetoacetate.2... 

The first products of the reaction are carbon monoxide and acetone dicarboxylic acid(I) the latter undergoes further partial decomposition into acetone(II) and carbon dioxide. 

Use may be made of the intermediate formation of acetone dicarboxylic acid and of the interaction of the latter with sodium nitroprusside solution to yield a red colouration as a test for citrates. When about 0-5 g of a citrate or of citric acid is treated with 1 ml concentrated sulphuric acid for 1 minute, the mixture cooled, cautiously diluted with water, rendered alkaline with sodium hydroxide solution and then a few millilitres of a freshly prepared solution of sodium nitroprusside added, an intense red colouration results. 

Tetramethyl-3-thietanone 1-oxide 400 is obtained in 69% yield by oxidation of the thietane with peracetic acid in benzene. Amides of 3-thietanone-2,4-dicarboxylic acid 1-oxide are said to be obtained by treatment of amides of acetone dicarboxylic acid with thionyl chloride and 3-thietanone-l-oxides may be intermediate in the reaction of ketones with thionyl chloride. The -oxide of 3,3,4,4-tetraphenyl-2-thietanone may be an intermediate in the oxidation of the thietanone by nz-chloroperbenzoic acid, which is discussed in Section XIII.4.E. ... 

But the most reliable biomimetic type of synthesis of tropine was achieved in 1S17 by Robinson (27). In this method, succindialdehyde, methylamine and acetone dicarboxylic acid were mixed at pH 5.6 for 30 minutes to give tropinone in one step which was then reduced to tropine by an established process (25). A much better yield (almost 40%) was obtained by using calcium acetcndicarboxy-late the calcium salt so produced is converted into tropinone by warming with hydrochloric acid (23). 

Elming et al. (30) have synthesized tropinone (in 81% yield) by using methylamine hydrochloride, acetone dicarboxylic acid and generating succindialdehyde m situ by the action of acid on 2, 5-dimethoxytetrahydrofuran which is commercially available. 

Galinovsky (119) has made the interesting observation that N-methylsuccinimide could be reduced by lithium aluminum hydride to a,a -dihydroxy-iV -methylpyiTolidine and this condensed with acetone-dicarboxylic acid to tropinone. 

Some slight decomposition of citrate also occurs. The main course of this appears to be via acetone dicarboxylic acid to form gaseous products—acetone, carbon dioxide, carbon monoxide, and water ... 

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